Project Summary/Abstract Parkinson?s disease is the second most common neurodegenerative disorder, with an estimated 59,000 new cases per year in the US, and as populations age it is expected to impose significant financial and social burden on society. Deep brain stimulation is an FDA approved treatment for PD, but despite a marked improvement in quality of life, DBS therapy is often inconsistent and can result in both cognitive and motor side effects. This may be due to a lack of understanding of the underlying mechanisms and structural pathways that mediate the therapeutic effects of DBS. This project seeks to identify the pathways responsible for the tremor improvements in STN DBS. In the long term, this research will refine DBS targeting and improve our overall understanding of the PD pathology. The first aim is to develop three-dimensional, patient-specific anatomical and tractography models. Ten patients and two fiber pathways will be modeled. Magnetic resonance images (MRI) will be used to define the geometry of relevant structures and the trajectory of relevant fiber pathways (i.e. cerebellothalamic and subthalamopallidal pathways), and computed tomography scans will be used to determine the location of the DBS electrode. This will result in ten patient-specific computational anatomical models including fiber tractography for use in DBS modeling. The second aim is to identify stimulation parameters that preferentially activate each specific pathway. Axons will be modeled using cable theory and their trajectories will be determined by probabilistic tractography. Multivariate statistical analyses will be used to analyze axon activation in response to stimulation. A numerical optimization algorithm will be used to determine specific stimulation paradigms that preferentially activate one pathway (i.e. the cerebellothalamic or subthalamopallidal pathway). The outcome of this aim will be a set of patient-specific stimulation parameters that will theoretically preferentially activate a specific fiber pathway. The third aim is to evaluate the clinical outcomes of these selective stimulation paradigms with regard to tremor to determine the effects of activation of each pathway. Quantitative motor assessments will be performed to assess preferential activation outcomes. We hypothesize that preferential activation of specific fiber pathways will result in different clinical outcomes, including variation in therapeutic benefit. Further, we hypothesize that modulation of the cerebellothalamic pathway is necessary and sufficient for tremor control. The completion of this aim will result in an improved understanding of the outcomes associated with preferential activation of the cerebellothalamic and subthalamopallidal pathways. Successful completion of this research will advance our understanding of how activation of specific fiber pathways can produce a therapeutic effect in PD patients.